(a) Field Of The Invention
This invention relates to compositions and methods for killing or controlling the growth of microorganisms and more particularly relates to certain substituted salicylamide compositions having anti-microbial activity which are particularly useful in controlling the growth of microorganisms related to dental plaques and associated diseases.
(b) History Of The Prior Art
Historically compositions and methods have been sought for killing and controlling the growth of microorganisms, particularly those related to disease. The compositions which have been used for this purpose all have had one or more disadvantages. For example the compositions have not been effective against all undesireable microorganisms such as disease causing bacteria, have permitted certain microorganisms to develop an immunity or tolerance for the composition, have been more toxic than desireable, have caused allergic reactions in the host, or have been expensive and difficult to manufacture or purify.
These disadvantages have been particularly noticeable in compositions used to control the growth of bacteria related to dental plaques and associated diseases. Prior art compositions used for this purpose are either insufficiently effective, are too toxic or both. Toxic as used here in means that the composition causes damage to an organism, especially a human, which uses the composition to control the growth of an undesired microorganism whether the composition is applied topically or otherwise.
Many compositions formerly and even currently in use as oral antiseptics, and for that matter many antiseptics for other uses, contain large quantities of chlorine or bromine, often attached to a phenyl amine ring. In general such aromatic amine chlorinated and brominated compounds are to be avoided due to toxicity and sometimes carcinogenicity often associated with this type of compound. Furthermore such compounds which have low enough toxicity to be used as oral antiseptics are usually not sufficiently effective at low concentrations to treat dental plaques and associated diseases.
An example of a compound which contains chlorine attached to a phenyl amine ring which is or has been used as an oral antiseptic is chlorhexidine. Another compound which has been used is tribromsalan, a brominated salicylanilide. This compound is effective but still is not as effective as desireable in killing or sufficiently inhibiting the growth of plaque causing organisms at concentrations as low as desired.
Compounds which are used as oral antiseptics which contain chlorine or bromine but not in a phenyl ring are cetylpyridinium chloride and domiphen bromide. These compounds are also insufficiently effective in controlling microorganisms associated with dental plaque, especially in dentifrice compositions in which these compounds often become deactivated. Other antiseptics which contain chlorine attached to a phenyl ring but are not generally used in oral antiseptics are hexachlorophene and triclocarban. A non-halogenated oral antiseptic is hexylresorcinal. Hexylresorcinal is insufficiently effective against plaque-forming organisms and in addition has a toxicity which is higher than desired. There are many other antiseptics but most have toxicities which are too high, especially for oral use.
Halogenated salicylanilides have been studied as possible antiseptic compounds; however, most halogenated salicylanilides have now been banned by the United States Food and Drug Administration from certain over-the-counter products. This ban is due to adverse effects resulting from the use of such products. For example tetrachlorosalicylanilide has been shown to produce allergic reactions in man and certain other halogenated salicylanilides have been reported to produce photo-allergic reactions.
It has been reported that certain tertiary butyl substituted salicylanilides are bactericides against the bacterium Staphylococcus aureus. To the time of the present invention it is not known what additional microorganisms might be affected by this compound and there is no indication that it might be effective against the traditionally difficult bacteria involved in dental plaques and associated diseases. (Japanese Pat. No. 75,129,738 Oct. 14, 1975)
There is therefore a need for an effective non-toxic antiseptic for general purpose use which may be, but is preferably not, halogenated with chlorine or bromine and there is definitely a need for an non-toxic antiseptic which is effective against the microorganisms associated with dental plaques and associated diseases.